Recent research has suggested that opioid administration alters susceptibility to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CMS), or associated neurological disorders including dementia. Current evidence indicates that initial transmission of the virus to the CMS involves trafficking of infected blood-derived monocytes during the acute phase of the infection. The traffic of monocytes to the CNS is a normal physiological process, but is augmented during inflammation and/or in association with infection of the brain. Evidence reported from our laboratory, as well as others, suggest that opioid drugs may promote the trafficking process that leads to migration of infected cells to the brain. Our hypothesis in this project is that opioids have a significant ability to alter the development of HIV encephalitis by altering the expression of critical chemokines and chemokine receptors. We believe that the opioid administration promotes the development of pro-inflammatory monocytes which possess an elevated capacity to both produce and respond to pro-inflammatory chemokines, and by virtue of greater trafficking capacity, accelerate the transit of virally infected cells into the brain. In specific aim 1, using SIV infection of macaques as a model for HIV infection, we will determine the effect of morphine, methadone, and opiate withdrawal on circulating levels of chemokines, and chemokine levels in the CNS. In addition, we will examine properties of circulating monocytes and T cells for the shift to a more pro-inflammatory cellular phenotype. In the second specific aim we will characterize the impact of the morphine administration on the activity and characteristics of effector and regulatory T cells. These studies will determine whether the influence of morphine, in the context of virus infection, induces a broad inflammatory polarization of T cell sub-populations. We will be able to determine whether the development of neuropathology in response to the SIV infection is altered by the opioid administration, and the results from this project will provide a very valuable mechanistic basis for the anticipated morphine effects.